PROJECT SUMMARY/ABSTRACT Individuals with bipolar mood disorders (BD) experience severe and episodic emotion dysregulation. Our existing pharmacological and psychosocial treatments fail to normalize emotion dysregulation for many bipolar patients. We need new and innovative approaches to help improve emotion dysregulation for these patients. The long-term goal of this proposal is to understand the pathophysiology of emotion dysregulation in BD, and to develop strategies to directly target and improve emotion regulation capacity. To this end, the candidate proposes: (1) training objectives to acquire expertise in advanced network-based analysis of neuroimaging data and training in the use of transcranial magnetic stimulation (TMS) as a translational clinical and research tool; (2) a research objective to identify patient-specific biomarkers of emotion dysregulation in BD and to experimentally engage these targets using TMS; (3) a team of mentors and advisors to ensure the candidate’s success, with expertise in bipolar disorder pathology and treatment (Dr. Andrew Nierenberg), advanced network analysis of neuroimaging data (Dr. Randy Buckner), clinical and research applications of TMS (Dr. Mark George and Dr. Joan Camprodon), neuromodulation of mood disorders (Dr. Darin Dougherty), emotion regulation (Dr. James Gross), task-based neuroimaging in BD (Dr. Thilo Deckersbach), and advanced statistical methods (Dr. Mark Vangel). The central hypothesis of the research proposal is that neuromodulation of patient-specific targets of emotion regulation-related neurocircuitry using TMS will enhance the capacity for emotion regulation in BD. The rationale for this proposal is that existing treatments don’t adequately address severe emotion dysregulation in BD, thus new innovative approaches are needed. This project has the potential to provide preliminary evidence for the future development of TMS as an innovative treatment strategy that can be used adjunctive to existing treatments to improve emotion regulation in BD. Specific aims proposed are: 1) to identify patient-specific pathophysiological markers of implicit and explicit emotion dysregulation in BD; 2) to determine the effect of TMS on emotion regulation circuit dynamics in BD; and 3) to determine the effect of TMS on emotion regulation behavioral responses in BD. The approach is innovative in that it uses a patient- specific, precision medicine approach with combined TMS-fMRI to target and probe emotion dysregulation at the level of neurocircuitry. The proposed research is significant, because it is has the potential to advance our understanding of the pathophysiology of emotion dysregulation in BD and will provide crucial pilot data towards testing the efficacy of TMS for improving emotion dysregulation in BD patients. Overall, the candidate will use this project and its associated training to transition and expand this work into an independent program of research developing neuroscience-informed interventions for bipolar mood disorders.

PROJECT NARRATIVE Bipolar disorders are chronic and debilitating, associated with significant personal and public health costs. The proposed research seeks to address the need to improve treatments for bipolar mood disorders by examining neuromodulation as a new, non-invasive approach to improving treatments for bipolar patients.